Project summary There is a growing body of evidence that obesity is associated with reduced cerebral metabolism; however, the underlying mechanisms and the functional clinical implications of these observations remain unclear. The central goal of this project is to investigate a finding we have recently made that obesity is associated with decreased transport capacity for glucose across the blood-brain barrier. Furthermore, this association may be mediated by circulating fatty acids. This proposal uses state of the art neuroimaging technology coupled with classic human metabolic phenotyping methodologies to investigate the underlying mechanisms behind how the brain is impacted by obesity. Aim 1 of this project will determine whether obesity is associated with changes in brain glucose transport and metabolism using 13C magnetic resonance spectroscopy scanning. Aim 2 of this project will use a randomized controlled study design to assess whether acute elevations of circulating fatty acid levels amongst lean, healthy control subjects will lead to decreased brain glucose levels. Finally, Aim 3 of this project will use parallel studies using a rat model to investigate the underlying cellular mechanisms. Because the brain is exquisitely sensitive to circulating glucose levels, the findings from this proposed study will help clarify how diminished brain glucose transport in obesity may lead to diminished post-prandial satiety signaling and/or be a potential mechanism for the neurocognitive consequences of obesity.